Androstane carbothioic acids

ABSTRACT

Androstane carbothioic acids of the formula: ##STR1## wherein R 1  represents a hydrogen atom, a hydroxy group in the α-configuration, a methyl group which may be in either the α- or β-configuration, or a methylene group; 
     R 2  represents a hydroxy or protected hydroxy group in either the α- or β-configuration or an oxo group; 
     R 3  represents a hydrogen, bromine, chlorine or fluorine atom; or R 2  and R 3  together represent a carbon-carbon bond or an epoxy group in the β-configuration; 
     R 4  represents a hydrogen or fluorine atom; and the symbol represents a single or double bond and the salts thereof are useful as intermediates in the preparation of anti-inflammatory androstane 17β-carbothioate esters. 
     The compounds of formula I are prepared by reaction of a reactive derivative of a 17β-carboxylic acid corresponding to the compound of formula I with hydrogen sulphide or a sulphide or hydrosulphide salt.

This application is a continuation of application Ser. No. 513,396 filedJuly 14, 1983, now U.S. Pat. No. 4,578,221; which is a continuation ofU.S. Ser. No. 408,837 filed Aug. 17, 1982; abandoned; which is acontinuation of U.S. Ser. No. 256,845 filed Apr. 23, 1981; abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to androstane 17α-hydroxy-17β-carbothioicacids and to processes for the preparation thereof. The compounds of theinvention are intermediates, primarily of use in preparinganti-inflammatory androstane 17β-carbothioate esters.

Anti-inflammatory steroids are most typically of the corticoid type,i.e. in the pregnane series. Certain androstane compounds containing avariety of carbothioate groupings in the 17β-position have been found topossess anti-inflammatory properties. In particular such androstanecompounds are described and claimed in U.S. patent application Ser. No.234,113 filed by G. H. Phillipps, B. M. Bain, C. Williamson, I. P.Steeples and S. B. Laing on Feb. 13, 1981.

In general, these anti-inflammatory androstane 17β-carbothioates havethe partial formula ##STR2## where R^(a) represents a C₁₋₆ alkyl group,a C₁₋₂ alkyl group carrying a terminal halogen atom, or a benzyl groupwhich may be substituted by a C₁₋₄ alkyl or C₁₋₄ alkoxy group or ahalogen atom; and OR^(b) represents a group --OCOR^(d), where R^(d)represents a hydrogen atom or a C₁₋₅ alkyl group and R^(c) represents ahydrogen atom or a methyl group (in either the α- or β-configuration) ora methylene group or OR^(b) and R^(c) together represent a 16α,17α-isopropylidenedioxy group. They may be generally represented by theformula: ##STR3## wherein R^(a), R^(b) and R^(c) are as previouslydefined; R^(e) represents a hydrogen, fluorine or chlorine atom ineither the α- or β-configuration; R^(f) represents a hydrogen, fluorine,chlorine or bromine atom; R^(g) represents a hydrogen, fluorine, orchlorine atom; R^(h) represents a hydroxy group in the β-configurationor a keto group or, when R^(g) represents a chlorine atom, a chlorine orfluorine atom in the β-configuration; R^(i) represents a hydrogen atomor where a 1,2-double bond is present, optionally a chlorine or bromineatom and the symbol represents a single or double bond.

DESCRIPTION OF THE INVENTION

We have now discovered that 17α-hydroxy-17β-carbothioic acids, whichhave not hitherto been described, may readily be prepared and serve asuseful intermediates, for example, in the preparation of suchanti-inflammatory androstane compounds.

Thus according to one feature of the present invention we provide17α-hydroxyandrostane 17β-carbothioic acids of the formula: ##STR4##wherein

R¹ represents a hydrogen atom, a hydroxy group in the α-configuration, amethyl group which may be in either the α- or β-configuration, or amethylene group;

R² represents a hydroxy or protected hydroxy group in either the α- orβ-configuration or an oxo group;

R³ represents a hydrogen, bromine, chlorine or fluorine atom; or R² andR³ together represent a carbon-carbon bond or an epoxy group in theβ-configuration;

R⁴ represents a hydrogen or fluorine atom; and the symbol represents asingle or double bond and the salts thereof.

Compounds of formula (I) and salts thereof which are particularly usefulintermediates for preparing androstane 17β-carbothioates include thosein which R¹ represents a hydrogen atom, an α- or β-methyl group or amethylene group.

Preferred compounds of formula I and salts thereof by virtue of theirutility as intermediates for preparing androstane 17β-carbothioates withhigh anti-inflammatory activity, include those compounds in which R¹represents a methyl group in the α- or β-configuration or a methylenegroup; R³ represents a fluorine atom; R⁴ represents a hydrogen atom or afluorine atom, R² represents a hydroxy group in the β-configuration oran oxo group, and the symbol in the 1,2-position represents acarbon-carbon double bond; and salts thereof.

Especially preferred compounds of formula I thus include, for example,the following:

9α-Fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;

9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;

9α-Fluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;

9α-Fluoro-17α-hydroxy-16α-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;

9α-Fluoro-11β,17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;

9α-Fluoro-17α-hydroxy-16-methylene-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;

6α,9α-Difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof; and

6α,9α-Difluoro-17α-hydroxy-16α-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof.

Protected hydroxy groups at the 11-position include for exampletrialkylsilyloxy e.g. trimethylsilyloxy groups or perfluoro orchloroalkanoyloxy e.g. trifluoroacetoxy groups.

Salts of the carbothioic acids of formula I include, for example alkalimetal, e.g. lithium, sodium or potassium salts; alkaline earth metale.g. calcium or magnesium salts; tertiary amine salts, e.g. pyridiniumor triethylammonium salts; or quaternary ammonium salts, e.g. tetrabutylammonium salts.

The above mentioned 17β-carbothioic acids and their salts may, forexample, be prepared by reaction of a reactive derivative of a17β-carboxylic acid having the formula ##STR5## (wherein) R¹, R², R³ andR⁴ are as herein defined) with hydrogen sulphide or a sulphide orhydrosulphide salt. Where a salt is used, the product having the formulaI will be in salt form. In general, the cation of the sulphide orhydrosulphide salt may be as described above in relation to compounds offormula I, for example an alkali metal salt such as sodium or potassiumhydrogen sulphide. The above-mentioned reactive derivative is preferablya 17α-hydroxy-androstane represented by the formula ##STR6## (whereinR¹, R², R³ and R⁴ are as herein defined and R⁵ represents a group of theformula ##STR7## in which X, Y and Z, which may be the same ordifferent, each represents CH or N, one or two of X, Y and Z being N,the heterocyclic ring optionally being substituted on at least onecarbon atom by a lower alkyl group (e.g. with 1 to 4 carbon atoms, suchas a methyl group) and/or where the heterocyclic ring contains twoadjacent carbon atoms, the said ring optionally carrying a benzene ringfused to the said adjacent carbon atoms).

The reactive derivatives of formula III are preferably prepared byreacting the carboxylic acid of formula II with a symmetric orasymmetric compound of the formula:

    R.sup.5 --W--R.sup.5                                       IV

wherein W represents the group CO, CS, SO or SO₂ and the groups R⁵,which may be the same or different, have the above meanings.

The compounds of formula IV are conveniently symmetric. In general,compounds of formula IV in which W represents CO, CS or SO will be used.Thus, for example, especially useful compounds of formula IV includeN,N'-carbonyldi(1,2,4-triazole), N,N'-carbonyldibenzotriazole,N,N'-carbonyldibenzimidazole, N,N'-carbonyldi(3,5-dimethylpyrazole),N,N'-thionyldiimidazole and especially N,N'-carbonyldiimidazole andN,N'-thiocarbonyldiimidazole.

The preparation of a compound having the formula I as herein defined isconveniently effected by reaction of a carboxylic acid having theformula II with a compound of formula IV followed by reaction of theintermediate product having the formula III thereby obtained withhydrogen sulphide or a salt thereof preferably in situ without isolationof the intermediate.

The reaction with the compound of formula IV is conveniently effected inthe presence of an inert anhydrous solvent e.g. a substituted amidesolvent such as N,N-dimethylformamide or N,N-dimethylacetamide,desirably in the absence of water, advantageously at or below ambienttemperature e.g. at a temperature of from -30° C. to +30° C. Thereaction is conveniently effected under approximately neutralconditions, advantageously in an inert atmosphere, e.g. under nitrogen.The same solvents and conditions are also applicable to the subsequentreaction with H₂ S or a salt thereof. The heterocyclic compound e.g.imidazole or 1,2,4-triazole formed as a by-product may, for example, bereadily removed by extraction with dilute acid.

In the starting 17α-hydroxy-17β-carboxylic acids having the formula IIthe 16-position will conveniently be substituted by the R¹ groupingdesired in the final product. They may be prepared in conventionalmanner, e.g. by oxidation of an appropriate 21-hydroxy-20-keto pregnane.

The oxidative removal of the 21-carbon atom of the pregnane startingmaterial may be effected for example with periodic acid, in a solventmedium and preferably at room temperature. Alternatively, sodiumbismuthate may be employed to effect the desired oxidative removal ofthe 21-carbon atom of a 17α-acyloxy pregnane compound, followed byhydrolysis to the corresponding 17α-hydroxy compound.

As will be appreciated should the starting pregnane compound contain anysubstituent sensitive to the above described oxidation, such a groupshould be suitably protected.

As stated above the compounds of formula I are intermediates useful inthe production of 17β-carbothioate esters and thus according to afurther feature of the present invention there is provided a process forpreparing an androstane 17α-hydroxy-17β-carbothioate represented by theformula ##STR8## (wherein R¹, R², R³ and R⁴ are as herein defined andR^(a) represents a C₁₋₆ alkyl group, or C₁₋₂ alkyl group carrying aterminal halogen atom or a benzyl group which may be substituted by aC₁₋₄ alkyl or C₁₋₄ alkoxy group or a halogen atom and the symbolrepresents a single or double bond which comprises esterifying the17β-carbothioic acid group of an androstane of formula I or a saltthereof. Any other reactive groups present in the molecule may besuitably protected as desired.

Thus for example, in order to prepare a S-methyl or S-ethyl ester the17β-carbothioic acid may be reacted with an appropriate diazoalkane,e.g. diazomethane, the reaction being preferably effected in a solventmedium, e.g. ether, tetrahydrofuran or methanol, and at a lowtemperature, preferably at -5° to +30° C. More preferably, a salt of theparent 17β-carbothioic acid for example, an alkali metal, e.g. lithium,sodium or potassium , salt or an alkylammonium, e.g. triethylammonium ortetrabutylammonium, salt may be reacted with an appropriate alkylatingor aralkylating agent, preferably in a polar solvent such as a ketone,e.g. acetone or an amide such as dimethylformamide, dimethylacetamide orhexamethylphosphoramide, conveniently at a temperature of 15° to 100° C.For example, for the preparation of an S-alkyl such as a S-methyl orS-ethyl or S-aralkyl such as S-benzyl 17β-carbothioate, the alkylatingor benzylating agent may comprise an alkyl or benzyl halide e.g. theiodide or bromide, or a dialkyl sulphate e.g. dimethylsulphate, or anO-alkyl-N,N'-dicyclohexylisourea. For the preparation of compounds inwhich R^(a) represents a haloalkyl group, the alkylating agent maycomprise an appropriate dihalo compound i.e. one containing a furtherhalogen atom (preferably a bromine or iodine atom) in addition to thehalogen atom of the desired R^(a) group. This process is particularlyapplicable to the preparation of compounds in which R^(a) is achloromethyl group, the alkylating agent advantageously beingbromochloromethane.

The esterification (i.e. the introduction of R^(a) into a compound offormula I) may also be effected in a multi-stage process, especiallywhere R^(a) represents a haloalkyl group. Thus, for example, the COSHgroup of the 17α-hydroxy-17β-carbothioic acid of formula I especially insalt form, may be converted to the group --COS(CH₂)_(n) Y (wherein Yrepresents a displaceable substituent and n is 1 or 2)at the17β-position, for example by conversion of the said acid or salt thereofto the corresponding hydroxyethyl thioester, e.g. with a halohydrin suchas 2-iodoethanol, followed by substitution of the hydroxy group in the2'-hydroxyethyl group by Y. Y may for example represent an alkyl- oraryl-sulphonyloxy group e.g. a mesyloxy or tosyloxy group.

A 2'-haloethyl 17β-carbothioate compound of formula V may then beprepared for example from a corresponding compound of formula I havingas 17β-substituent the group --COS(CH₂)_(n) Y (wherein n=2 and Y is ashereinbefore defined) by reaction with an appropriate alkali metal,alkaline earth metal or quaternary ammonium halide, e.g. lithiumchloride, conveniently in a solvent medium, e.g. acetone,dimethylformamide, hexamethylphosphoramide or ethanol.

Fluoromethyl or 2'-fluoroethyl-17β-carbothioate compounds of formula (I)may also be prepared from the corresponding chloro or more preferablybromo or iodo compounds by reaction with an appropriate fluoride, e.g.silver monofluoride or silver difluoride, conveniently in a solvent, forexample acetonitrile.

It will be appreciated that one advantage of the compounds of theinvention as intermediates in the preparation of products having formula(B) is that they permit the formation of 17β-carbothioates when thecorresponding thiols are not conveniently available.

The active final products into which the intermediates having theformula I may be converted generally possess a 17α-acyloxy or16α,17α-acetonide grouping and thus according to a still further featureof the present invention there is provided a process for the preparationof androstane 17β-carbothioic acids and salts thereof represented by theformula: ##STR9## (wherein R², R³ and R⁴ are as herein defined; OR^(b)represents a group --OCOR^(d) where R^(d) represents a hydrogen atom ora C₁₋₅ alkyl group; and R^(c) is as defined for R¹ ; or OR^(b) and R^(c)together represent a 16α,17α-isopropylidenedioxy group and the symbolrepresents a single or double bond), which process comprises esterifyingthe 17α-hydroxy group of an androstane having the formula I or reactionwith acetone to convert the 16α,17α-diol grouping, where present, to the16α,17α-acetonide grouping. Any other reactive groups present in themolecule may be suitably protected as desired.

The esterification of the 17α-hydroxy group may, if desired, be effectedby conventional techniques, e.g. by reacting the parent 17α-hydroxycompound with a mixed anhydride of the required carboxylic acid, whichmay, for example, be generated in situ by reacting the carboxylic acidwith an appropriate anhydride such as trifluoroacetic anhydride,preferably in the presence of an acid catalyst, e.g. p-toluenesulphonicacid or sulphosalicylic acid. Alternatively, the mixed anhydride may begenerated in situ by reaction of a symmetrical anhydride of the requiredacid with an appropriate further acid, e.g. trifluoroacetic acid.

The reaction is advantageously effected in an organic solvent mediumsuch as benzene, methylene chloride or an excess of the carboxylic acidemployed, the reaction being conveniently effected at a temperature of20°-100° C.

Alternatively, the 17α-hydroxy group may be esterified by reaction ofthe parent 17α-hydroxy compound with the appropriate acid anhydride oracid chloride, if desired, in the presence of non-hydroxylic solvents,e.g. chloroform, methylene chloride or benzene, and preferably in thepresence of a strong acid catalyst, e.g. perchloric acid,p-toluenesulphonic acid or a strongly acidic cation exchange resin, e.g.Amberlite IR 120, the reaction being conveniently effected at atemperature of 25° to 100° C.

The esterification of the 17α-hydroxy group may, if desired be effectedby reacting the parent 17α-hydroxy-17β-carbothioic acid with theappropriate carboxylic acid chloride, preferably in a solvent such as ahalogenated hydrocarbon e.g. dichloromethane, and advantageously in thepresence of a base such as triethylamine, preferably at a lowtemperature e.g. 0° C.

Where a compound having the formula I is used in which R¹ represents anα-hydroxy group, the corresponding 16α,17α-acetonide 17β-carbothioicacid may conveniently be prepared by reaction of the16α,17α-dihydroxy-17β-carbothioic acid with acetone in the presence of astrong acid e.g. toluene p-sulphonic acid.

The foregoing reactions may also be carried out on compounds having avariety of substituents or groupings which are subsequently convertedinto those present in the compounds of formulae I, V or VI as definedabove.

Those compounds of formulae I, V or VI having an 11β-hydroxy group maythus be prepared by reduction of a corresponding 11-oxo compound, e.g.using an alkali metal or alkaline earth metal borohydride, e.g. sodiumor calcium borohydride, conveniently in an alcoholic or aqueousalcoholic solvent such as methanol or ethanol.

Such an 11-keto compound may be prepared by oxidation of a corresponding11α-hydroxysteroid, for example using a chromic acid reagent such asJones' reagent.

An 11β-hydroxy compound of formula II may also be obtained bydeprotection of a corresponding compound having a protected hydroxygroup at the 11β-position, for example a trialkylsilyloxy group such asthe trimethylsilyloxy group or a perfluoroalkanoyl group such as thetrifluoroacetyl group. The alkyl groups in such a trialkylsilyloxy grouppreferably each contain 1-6 carbon atoms. Removal of the protectinggroup may be effected by hydrolysis, the trialkylsilyl group, beingreadily removed by mild acid or basic hydrolysis or particularlyconveniently using a fluoride e.g. hydrogen fluoride or an ammoniumfluoride. The perfluoro- or chloro-alkanoyl protecting group may also beremoved by mild acid or basic hydrolysis, but preferably under acidicconditions when there is a 9α-chlorine atom. Such a protected hydroxylgroup may be introduced, for example, by reacting a 11β-hydroxy steroidwith an appropriate reagent such as a trialkylsilyl halide or aperfluoro- or chloro-alkanoic anhydride.

Compounds of formulae I, V or VI having a 3-keto group may be obtainedby deprotection of a corresponding compound having a protected ketogroup at the 3-position, for example an enol ether or ester grouping.Such a grouping may be deprotected by, for example, hydrolysis e.g. acidhydrolysis. An enol ether or ester grouping may be introduced by, forexample, known techniques such as reaction of the 3-ketone with anetherifying or esterifying reagent under enolising conditions.

Compounds of formulae I, V or VI having a 9α-halogen atom and an11β-hydroxyl group may also be produced by reaction of a correspondingcompound having a 9,11-double bond (and no substituent in the11-position) with reagents serving to introduce the required9α-halo-11β-hydroxy grouping. This may involve initial formation of abromohydrin by reaction with an N-bromo-amide or -imide such asN-bromosuccinimide, followed by formation of the corresponding9β,11β-epoxide by treatment with a base and reaction of the epoxide withhydrogen fluoride or hydrogen chloride to introduce the requiredfluorohydrin or chlorohydrin grouping respectively. Alternatively, the9,11-olefin compound may be reacted with an N-chloro-amide or -imide tointroduce the required 9α-chloro-11β-hydroxy grouping directly.

Compounds of formulae I, V or VI having a 4,5-double bond canconveniently be prepared by partial reduction of the corresponding Δ¹,4-compound, for example, by hydrogenation using a palladium catalyst,conveniently in a solvent e.g. ethyl acetate or by homogeneoushydrogenation using for example tris(triphenylphosphine)rhodiumchloride, conveniently in a solvent such as benzene, or byexchange-hydrogenation using for example cyclohexene in the presence ofa palladium catalyst in a solvent e.g. ethanol, preferably under reflux.This reduction may be carried out on a haloalkyl ester where this issufficiently stable in such a reaction or may be effected at an earlierstage.

Compounds of formula I, V or VI having a fluorine atom in the 6-positioncan also be prepared, from the corresponding 3-enol ester or etherfollowed by reaction with an electrophilic fluorinating agent such asperchloryl-fluoride and subsequent hydrolysis to yield the corresponding6β-fluoro compound. Where no 1,2-double bond is present, treatment witha strong acid such as hydrogen chloride or more preferably hydrogenbromide effects epimerisation to form the 6α-fluoro compound. Theepimerisation is preferably effected in a non-aqueous solvent medium,dioxan being particularly preferred; other solvents which may be usedinclude tetrahydrofuran, ester solvents such as ethyl acetate, ketonesolvents and amide solvents such as dimethylacetamide ordimethylformamide. The epimerisation is also advantageously effected inthe presence of a carboxylic acid such as acetic acid, especially whenhydrogen bromide is employed. In the case of Δ¹,4 -compounds, suchepimerisation is sometimes difficult and it is preferable to hydrogenatethe 1,2-double bond, e.g. by catalytic hydrogenation, effect theepimerisation and re-introduce the 1,2-double bond by dehydrogenation,normally under neutral or mildly acidic conditions e.g. usingdichloro-dicyanoquinone or chloranil.

Where it is desired to prepare an anti-inflammatory compound having an11β-hydroxy group it may be convenient to effect the necessary reactionson the corresponding 11-keto compound, the 11-ketone compound beingconverted to the corresponding 11β-hydroxy group as the last stage inthe reaction sequence.

It will be appreciated that the above-mentioned anti-inflammatorycompounds of formula (A) may, be readily prepared from correspondingcompounds of formula V by esterification of the free 17α-hydroxy group,or from corresponding compounds of formula VI by esterification of thefree 17β-carbothioic acid group or a salt thereof. The esterification ofthe free 17α-hydroxy group in the compounds of formula V may, forexample, be effected as described in relation to the esterification ofthe free 17α-hydroxy group in the compounds of formula I. Similarly theesterification of the free 17β-carbothioic acid group or a salt thereofin the compounds of formula VI may, for example, be effected asdescribed in relation to the esterification of the free 17β-carbothioicacid group or a salt thereof in the compounds of formula I.

9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carboxylicacid is believed to be a novel compound and thus constitutes a stillfurther feature of the present invention. This novel compound may forexample be prepared by oxidative removal of the 21-carbon atom from9α-fluoro-17,21-dihydroxy-16β-methylandrosta-1,4-diene-3,11,20-trioneaccording to conventional techniques e.g. by reaction with periodicacid, conveniently in a solvent medium e.g. tetrahydrofuran andpreferably at about ambient temperature e.g. from 0° to 30° C.

The following Examples illustrate the present invention.

Melting points were determined in °C. on a Kofler block and areuncorrected. Optical rotations were determined at room temperature andsolutions were dried over magnesium sulphate unless otherwise stated.

EXAMPLE 19α-Fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicAcid

A stirred solution of9α-fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carboxylicacid (0.502 g) in dry N,N-dimethylformamide (15 ml) was cooled at -5°under nitrogen and treated with N,N'-carbonyldiimidazole (0.435 g) andthe reaction was stirred at -5° for 18 hrs. Hydrogen sulphide gas wasbubbled into the reaction for 20 min and the solution was stirred for afurther 4 hrs, gradually being allowed to warm to 22°. The reaction waspoured into ethyl acetate and the resulting solution was washed with2N-hydrochloric acid and water, then extracted with 2N-sodium carbonatesolution (3×50 ml). The combined extracts were washed with ethyl acetate(60 ml) then covered with further ethyl acetate (100 ml) and acidifiedwith hydrochloric acid to pH 1.0. The aqueous layer was extracted withfurther ethyl acetate and the extracts were washed with water andsaturated sodium chloride solution, then dried and the solvent wasremoved in vacuo to give a white solid which was crystallised twice fromethyl acetate to give the title carbothioic acid (0.315 g) m.p. 198° to201° (dec), [α]_(D) +189° (c 0.71, dioxan).

EXAMPLE 29α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicAcid

A stirred solution of9α-fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carboxylicacid (5.587 g) in dry N,N-dimethylformamide (150 ml) at 20° undernitrogen was treated with N,N'-carbonyldiimidazole (4.847 g) and thereaction was stirred at 20° for 4 hrs. Hydrogen sulphide gas was bubbledinto the reaction for 10 min and the solution was stirred for a furtherhour. The solution was poured onto ice (300 ml) and 2N-hydrochloric acid(100 ml) to give a buff precipitate. This was filtered off, air driedovernight (6.268 g) and crystallised from ethyl acetate to give thetitle carbothioic acid (3.761 g) as white prisms, m.p. 215° to 218°,[α]_(D) +143°[c 0.88, dimethylformamide].

EXAMPLE 39α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicAcid

A stirred solution of9α-fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carboxylicacid (1.059 g) in dry N,N-dimethylformamide (50 ml) at 20° undernitrogen was treated with N,N'-thiocarbonyldiimidazole (1.368 g) and thereaction was stirred at 20° for 4 hrs. Hydrogen sulphide gas was bubbledinto the reaction for 5 min. and the solution was stirred for a furtherhour. The reaction was partitioned between ethyl acetate (100 ml) and2N-hydrochloric acid (100 ml) and the organic phase was washed with2N-hydrochloric acid (100 ml) and water (2×100 ml) and was extractedwith 2N-sodium carbonate solution (2×75 ml). The combined extracts werewashed with ethyl acetate (50 ml), then covered with ethyl acetate (100ml) and acidified with hydrochloric acid to pH 1. The aqueous layer wasextracted with further ethyl acetate (50 ml) and the combined extractswere washed with water (3×), saturated sodium chloride solution, dried,and the solvent was removed in vacuo. The residue was crystallied fromethyl acetate to give the title carbothioic acid (0.559), m.p. 212° to219°, [α]_(D) +145°[c 0.81, dimethylformamide].

EXAMPLE 4 S-Chloromethyl9α-fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate

A stirred solution of9α-fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicand (0.169 g) and sodium hydrogen carbonate (0.040 g) inN,N-dimethylformamide (6 ml) was treated with bromochloromethane (0.1ml) and stirring was continued at 22° for 1 hr. The reaction mixture wasdiluted with ethyl acetate (100 ml) and the solution was successivelywashed with 2N-hydrochloric acid (2×), water (2×), 2N-sodium carbonatesolution (2×), water (2×) and saturated sodium chloride solution, thendried (MgSO₄) and the solvent was removed in vacuo. The residue wascrystallised twice from ethyl acetate to give the title S-chloromethylthiolester (0.193 g) as white plates solvated with ethyl acetate (1mol), m.p. 126° to 130°, [α]_(D) +147.5° (c 0.64, dioxan).

EXAMPLE 59α-Fluoro-16β-methyl-3,11-dioxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioicAcid

A stirred solution of9α-fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid (0.485 g) and triethylamine (0.57 ml) in dichloromethane was cooledin ice-salt, treated with propionyl chloride (0.43 ml) and the reactionwas stirred at 0° for 1.5 hr. The mixture was partitioned between ethylacetate (75 ml) and 2N-sodium carbonate solution (75 ml) and the organiclayer was successively used with further 2N-sodium carbonate solution,water (2×), 2N-hydrochloric acid, water (2×), and saturated sodiumchloride solution, then dried and the solvent removed in vacuo to give ayellow crystalline solid (0.562 g). This was dissolved in acetone (10ml), diethylamine (1.0 ml) was added and the reaction was stirred at 22°for 1.25 hr. The solvents were removed in vacuo and the residue waspartitioned between ethyl acetate (30 ml) and 2N-hydrochloric acid (30ml). The ethyl acetate layer was washed with water (2×) and extractedwith 2N-sodium carbonate solution (2×30 ml). The combined extracts werewashed with ethyl acetate (30 ml) and covered with ethyl acetate (60 ml)and acidified to pH 1.0 with hydrochloric acid. The ethyl acetate layerwas washed with water (3×) and saturated sodium chloride solution, thendried (MgSO₄) and the solvent was removed in vacuo to give a white solidwhich was crystallised twice from ethyl acetate to give the title ester(0.290 g), m.p. 173° to 180°, [α]_(D) +148° (c 1.03, dioxan).

EXAMPLE 6 S-Chloromethyl9α-fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioate

A solution of9α-fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid (5.006 g), and sodium bicarbonate (1.612 g) inN,N-dimethylacetamide (50 ml) was treated with bromochloromethane (1.24ml) and the reaction was stirred at 22° for 3.3 hrs. The solution wasdiluted with ethyl acetate (70 ml) and washed successively with2N-hydrochloric acid, water, sodium metabisulphite solution, water (3×)and saturated sodium chloride solution, then dried and the solvent wasremoved in vacuo to give a cream solid (3.638 g). The analytical samplewas obtained after preparative t.l.c. (silica gel, developed withchloroform:acetone=9.1), and crystallised from ethyl acetate ascolourless prisms of the title ester (0.262 g), m.p. 223° to 228°,[α]_(D) +251° (c 1.2, dioxan).

EXAMPLE 7 S-Methyl9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioate

A solution of9α-fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid (1.009 g) and sodium hydrogen carbonate (0.458 g) inN,N-dimethylacetamide (10 ml) was treated with iodomethane (0.24 ml).The clear solution was stirred at 22° for 37 min. then partitionedbetween ethyl acetate (50 ml) and 2N-hydrochloric acid (50 ml). Theorganic layer was successively washed with water, saturated sodiumhydrogen carbonate solution, water (3×) and saturated sodium chloridesolution, then dried and the solvent was removed in vacuo to give awhite solid which was crystallised from ethyl acetate to give the titlemethyl thioester (0.492 g) as white plates, m.p. 242° to 248°, [α]_(D)+193° (c 0.76, dioxan).

EXAMPLE 89α-Fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioicAcid

A stirred solution of 9α-fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid(0.511 g)in dichloromethane (20 ml) containing triethylamine (0.6 ml)was cooled to 2° and treated with propionyl chloride (0.45 ml) and thereaction was stirred at 2° for 2.5 hrs. The reaction was partitionedbetween ethyl acetate and sodium hydrogen carbonate and the organicphase was washed with water, 2N-hydrochloric acid, water and saturatedsodium chloride solution, dried and the solvent removed in vacuo to givea colourless solid (0.634 g).

This was dissolved in acetone (30 ml), diethylamine (1.5 ml) added andthe clear solution stirred at 22° for 55 min. The reaction was dilutedwith ethyl acetate (50 ml) and was washed with 2N-hydrochloric acid andwater then extracted with 5% sodium carbonate solution. The combinedextracts were acidified with 2N-hydrochloric acid to pH 1 and extractedwith ethyl acetate. The combined extracts were washed with water andsaturated sodium chloride solution and dried and the solvent removed togive a colourless froth (0.522 g) which was crystallised from ethylacetate to give the title ester as colourless prisms (0.307 g) mp 174°to 179°, [α]_(D) +107 (c 1.0, dioxan).

EXAMPLE 99α-Fluoro-11β,17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-carbothioicAcid

A solution of9α-fluoro-11β,17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-carboxylicacid (0.218 g) in dry N,N-dimethylformamide (10 ml) at 22° undernitrogen was treated with N,N'-carbonyldiimidazole (0.254 g) and thereaction was stirred at 22° for 4 hrs. Hydrogen sulphide gas was bubbledinto the reaction for 5 min and the mixture, now pale green, was stirredfor 1 hr at 22°. The mixture was diluted with ethyl acetate (150 ml) andthe solution was washed with 2N-hydrochloric acid, water and saturatedsodium chloride solution, dried and the solvent removed in vacuo to givea yellow froth (0.222 g) which was crystallised twice from ethyl acetateto give the title carbothioic acid (0.078 g) as white prisms, decomposedat ca. 250° without melting, [60 ]_(D) +117° (c 0.32, dioxan).

EXAMPLE 10 9α-Fluoro-11β,17α-dihydroxy-3-oxoandrosta-1,4-diene-17.beta.-carbothioic acid

A solution of9α-fluoro-11β,17α-dihydroxy-3-oxoandrosta-1,4-diene-17.beta.-carboxylicacid (4.5 g) in dry N,N-dimethylformamide (100 ml) was stirred undernitrogen with N,N'-carbonyldiimidazole (4.04 g) at 22° C. for 4 h.Hydrogen sulphide was then passed through the solution for 30 min andthen kept for a further 15 min. The mixture was poured into a mixture of2N-hydrochloric acid (250 ml) and ice (ca 100 g) and the resultingprecipitate was collected, washed with water and dried to give a whitesolid (4.56 g). A portion (120 mg) was recrystallised from ethanol togive the title thioacid as colourless crystals (70 mg), m.p. 222°-225°,[α]_(D) +116° (c 0.57, dioxan).

EXAMPLE 116α,9α-Difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid

A solution of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylicacid (12.0 g) in dry N,N-dimethylformamide (250 ml) was stirred andtreated with N,N'-carbonyldiimidazole (9.94 g) under nitrogen at roomtemperature. After 4 h, hydrogen sulphide was passed through thesolution for 0.5 h and the mixture was kept for a further 0.5 h. Thereaction mixture was poured into 2N-hydrochloric acid (500 ml)containing ice (ca 250 g). The resulting precipitate was collected,washed with water and dried in vacuo to give the title thioacid as awhite solid (11.47 g), m.p. 230°-232°, [α]_(D) +94° (c 0.91, dioxan).

EXAMPLE 12 17α-Acetoxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid

A solution of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoadrosta-1,4-diene-17β-carbothioicacid (1.625 g) and triethylamine (2.0 ml) in dichloromethane (75 ml) wasstirred at ca 0° C., treated dropwise with acetyl chloride (1.275 ml),then stirred at this temperature for 1.25 h. The mixture was washed with2N-sodium carbonate (50 ml), water, 2N-hydrochloric acid (50 ml), water(3×50 ml), brine (50 ml), then dried and evaporated to a white solid(1.91 g). This was dissolved in acetone (40 ml) and stirred withdiethylamine (4 ml) at 27° C. for 45 min. The mixture was concentratedto ca 25 ml and poured into 2N-hydrochloric acid (100 ml) containing ice(ca 100 g): after being stirred the resulting precipitate was collected,washed with water and dried to give a solid (1.685 g). A portion (400mg) was recrystallised from ethyl acetate to give the title 17α-acetate(280 mg), m.p. 175°-177°.

EXAMPLE 1317α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid

Using a similar procedure to that described in Example 12,6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid (2.0 g) was converted, with butyryl chloride (1.5 ml) instead ofacetyl chloride, to the title 17α-butyrate (2.08 g). A portionrecrystallised from ethyl acetate had m.p. 155°-157°.

EXAMPLE 149α-Fluoro-11β-hydroxy-3-oxo-17α-propionyloxyandrosta-1,4-diene-17β-carbothioicacid

Using a similar procedure to that described in Example 12,9α-fluoro-11β,17α-dihydroxy-3-oxoandrosta-1,4-diene-17.beta.-carbothioicacid (3.8 g) was converted, using propionyl chloride (3.9 ml) instead ofacetyl chloride and after aminolysis of the intermediate withdiethylamine (10.35 ml), into the title 17α-propionate (4.17 g). Aportion (350 mg) recrystallised from ethyl acetate gave colourlesscrystals (165 mg), m.p. 135°-138°, [α]_(D) +72° (c 0.92, dioxan).

EXAMPLE 156α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17.alpha.-propionyloxyandrosta-1,4-diene-17β-carbothioicacid

A solution of6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid (5.0 g) and triethylamine (6.15 ml) in dichloromethane (140 ml) wascooled with ice-salt and treated dropwise with propionyl chloride (4.74ml). The reation mixture was stirred further at ca 0° C. for 0.75 h thenwashed successively with 2N-sodium carbonate, water, 2N-hydrochloricacid, water and brine. After being dried, solvent was removed to give awhite solid (6.35 g). This was redissolved in acetone (120 ml) anddiethylamine (12.5 ml): after being stirred at room temperature for 1 hthe volume was reduced to ca 75 ml. The solution was poured into2N-hydrochloric acid (200 ml) containing ice (ca 300 g) and theresulting precipitate was collected, washed with water and dried invacuo to a white solid (5.17 g) m.p. 152°-155°. Recrystallisation of aportion (400 mg) from ethyl acetate gave the analytically pure titlethioacid 17α-propionate as colourless crystals (290 mg), m.p. 161°-164°,[α]_(D) -27° (c 0.95, dioxan).

PREPARATION 19α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxandrosta-1,4-diene-17β-carboxylicacid

A stirred suspension of 9α-fluoro17,21-dihydroxy-16β-methylpregna-1,4-diene-3, 11, 20, trione (4.842 g)in tetrahydrofuran (50 ml) was cooled in ice and treated dropwise over 5min. with a solution of periodic acid (4.255 g) in water (15 ml). Thereaction was stirred at 22° for 2.25 hr, when most of the suspension haddissolved. The solvent was removed in vacuo, with periodic addition ofwater to maintain the original volume. The resulting precipitate wasfiltered off, washed with water and dried in air and in vacuo to givethe title carboxylic acid as cream prisms (4.55 g) mp 270° to 272°(dec), [α]_(D) +136° (c 1.04,dimethylsulphoxide).

PREPARATION 29α-Fluoro-11β,17α-dihydroxy-3-oxoandrosta-1,4-diene-17.beta.-carboxylicacid

A suspension of 9α-fluoroprednisolone (10 g) in dry tetrahydrofuran (55ml) was stirred and treated with a solution of periodic acid (9.0 g) inwater (90 ml) and the mixture was stirred at 22° C. for 2 h. It was thenpoured into iced-water (ca 400 ml) and, after being stirred for 15 min.,the solid product was collected, washed with water, and dried to givethe title acid as a solid (9.42 g). A portion recrystallised fromethanol had m.p. 289°-293° [α]_(D) +66 (c 0.73, methanol).

We claim:
 1. A compound of the formula ##STR10## wherein R¹ represents ahydrogen atom, a hydroxy group in the α-configuration, a methyl groupwhich may be in either the α- or β-configuration, or a methylenegroup;R² represents a hydroxy or protected hydroxy group in either theα- or β-configuration or an oxo group; R³ represents a hydrogen,bromine, chlorine or fluorine atom; or R² and R³ together represent acarbon-carbon bond or an epoxy group in the β-configuration; R⁴represents a hydrogen or fluorine atom; and the symbol represents asingle or double bond; and the salts thereof.
 2. A compound according toclaim 1 wherein R¹ represents a hydrogen atom, a methyl group in eitherthe α- or β-configuration, or a methylene group.
 3. A compound accordingto claim 1 wherein R¹ represents a methyl group in the α- orβ-configuration or a methylene group, R² represents a hydroxy group inthe β-configuration or an oxo group; R³ represents a fluorine atom; R⁴represents a hydrogen atom or a fluorine atom and the symbol representsa carbon-carbon double bond and the salts thereof.
 4. A compoundaccording to claim 1 selected from the group consistingof:9α-Fluoro-11β,17α-dihydroxy-16β-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;9α-Fluoro-17α-hydroxy-16β-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;9α-Fluoro-11β-17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;9α-Fluoro-17α-hydroxy-16α-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof;9α-Fluoro-11β,17α-dihydroxy-16-methylene-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof; and9α-Fluoro-17α-hydroxy-16-methylene-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof. 5.6α,9α-Difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof. 6.6α,9α-Difluoro-17α-hydroxy-16α-methyl-3,11-dioxoandrosta-1,4-diene-17β-carbothioicacid and the salts thereof.